Hypothermia effects on neuronal plasticity post spinal cord injury.

BACKGROUND: SCI is a time-sensitive debilitating neurological condition without treatment options. Although the central nervous system is not programmed for effective endogenous repairs or regeneration, neuroplasticity partially compensates for the dysfunction consequences of SCI. OBJECTIVE AND HYPOTHESIS: The purpose of our study is to investigate whether early induction of hypothermia impacts neuronal tissue compensatory mechanisms. Our hypothesis is that although neuroplasticity happens within the neuropathways, both above (forelimbs) and below (hindlimbs) the site of spinal cord injury (SCI), hypothermia further influences the upper limbs' SSEP signals, even when the SCI is mid-thoracic. STUDY DESIGN: A total of 30 male and female adult rats are randomly assigned to four groups (n = 7): sham group, control group undergoing only laminectomy, injury group with normothermia (37°C), and injury group with hypothermia (32°C +/-0.5°C). METHODS: The NYU-Impactor is used to induce mid-thoracic (T8) moderate (12.5 mm) midline contusive injury in rats. Somatosensory evoked potential (SSEP) is an objective and non-invasive procedure to assess the functionality of selective neuropathways. SSEP monitoring of baseline, and on days 4 and 7 post-SCI are performed. RESULTS: Statistical analysis shows that there are significant differences between the SSEP signal amplitudes recorded when stimulating either forelimb in the group of rats with normothermia compared to the rats treated with 2h of hypothermia on day 4 (left forelimb, p = 0.0417 and right forelimb, p = 0.0012) and on day 7 (left forelimb, p = 0.0332 and right forelimb, p = 0.0133) post-SCI. CONCLUSION: Our results show that the forelimbs SSEP signals from the two groups of injuries with and without hypothermia have statistically significant differences on days 4 and 7. This indicates the neuroprotective effect of early hypothermia and its influences on stimulating further the neuroplasticity within the upper limbs neural network post-SCI. Timely detection of neuroplasticity and identifying the endogenous and exogenous factors have clinical applications in planning a more effective rehabilitation and functional electrical stimulation (FES) interventions in SCI patients.

Polymeric Dendrimers as Nanocarrier Vectors for Neurotheranostics.

Dendrimers are polymers with well-defined 3D branched structures that are vastly utilized in various neurotheranostics and biomedical applications, particularly as nanocarrier vectors. Imaging agents can be loaded into dendrimers to improve the accuracy of diagnostic imaging processes. Likewise, combining pharmaceutical agents and anticancer drugs with dendrimers can enhance their solubility, biocompatibility, and efficiency. Practically, by modifying ligands on the surface of dendrimers, effective therapeutic and diagnostic platforms can be constructed and implemented for targeted delivery. Dendrimer-based nanocarriers also show great potential in gene delivery. Since enzymes can degrade genetic materials during their blood circulation, dendrimers exhibit promising packaging and delivery alternatives, particularly for central nervous system (CNS) treatments. The DNA and RNA encapsulated in dendrimers represented by polyamidoamine that are used for targeted brain delivery, via chemical-structural adjustments and appropriate generation, significantly improve the correlation between transfection efficiency and cytotoxicity. This article reports a comprehensive review of dendrimers' structures, synthesis processes, and biological applications. Recent progress in diagnostic imaging processes and therapeutic applications for cancers and other CNS diseases are presented. Potential challenges and future directions in the development of dendrimers, which provide the theoretical basis for their broader applications in healthcare, are also discussed.

Intranasal Delivery of Functionalized Polymeric Nanomaterials to the Brain.

Intravenous delivery of nanomaterials containing therapeutic agents and various cargos for treating neurological disorders is often constrained by low delivery efficacy due to difficulties in passing the blood-brain barrier (BBB). Nanoparticles (NPs) administered intranasally can move along olfactory and trigeminal nerves so that they do not need to pass through the BBB, allowing non-invasive, direct access to selective neural pathways within the brain. Hence, intranasal (IN) administration of NPs can effectively deliver drugs and genes into targeted regions of the brain, holding potential for efficacious disease treatment in the central nervous system (CNS). In this review, current methods for delivering conjugated NPs to the brain are primarily discussed. Distinctive potential mechanisms of therapeutic nanocomposites delivered via IN pathways to the brain are then discussed. Recent progress in developing functional NPs for applications in multimodal bioimaging, drug delivery, diagnostics, and therapeutics is also reviewed. This review is then concluded by discussing existing challenges, new directions, and future perspectives in IN delivery of nanomaterials.

Neuroprotective Role of Hypothermia in Acute Spinal Cord Injury.

Even nowadays, the question of whether hypothermia can genuinely be considered therapeutic care for patients with traumatic spinal cord injury (SCI) remains unanswered. Although the mechanisms of hypothermia action are yet to be fully explored, early hypothermia for patients suffering from acute SCI has already been implemented in clinical settings. This article discusses measures for inducing various forms of hypothermia and summarizes several hypotheses describing the likelihood of hypothermia mechanisms of action. We present our objective neuro-electrophysiological results and demonstrate that early hypothermia manifests neuroprotective effects mainly during the first- and second-month post-SCI, depending on the severity of the injury, time of intervening, duration, degree, and modality of inducing hypothermia. Nevertheless, eventually, its beneficial effects gradually but consistently diminish. In addition, we report potential complications and side effects for the administration of general hypothermia with a unique referment to the local hypothermia. We also provide evidence that instead of considering early hypothermia post-SCI a therapeutic approach, it is more a neuroprotective strategy in acute and sub-acute phases of SCI that mostly delay, but not entirely avoid, the natural history of the pathophysiological events. Indeed, the most crucial rationale for inducing early hypothermia is to halt these devastating inflammatory and apoptotic events as early and as much as possible. This, in turn, creates a larger time-window of opportunity for physicians to formulate and administer a well-designed personalized treatment for patients suffering from acute traumatic SCI.

Comparative analysis of functional assessment for contusion and transection models of spinal cord injury.

STUDY DESIGN: Descriptive secondary analysis of two spinal cord injury (SCI) animal models. OBJECTIVES: To compare the somatosensory evoked potential (SSEP) and motor behavioral (BBB) assessments of the two most used rodent SCI models (contusion and transection), to elucidate their functional similarity and differences over the acute phase of 3 weeks. SETTING: Neuro-electrophysiology SSEP and motor behavioral BBB assessments are used to provide a comparative analysis of the functional changes among various severities of contusion and transection SCI. METHODS: Adult male and female rats randomly grouped (n = 5) as following: mild (6.25 mm), moderate (12.5 mm), severe (25 mm), and very severe (50 mm) contusion as well as right T10 hemi-transection (RxI), left T8 and right T10 double hemi-transection (DxI), and T8 complete transection (CxI) injuries, plus the control group (laminectomy with no injury). Animal weight, body temperature, anesthesia, surgical procedures, electrophysiological SSEP monitoring, locomotion BBB scoring, and statistical analysis were identical among all animal groups. RESULTS: Statistical analysis of the SSEP and BBB data from both contusion and transection injury models indicate significant differences (P < 0.05). The results also show remarkable similarity for the severe and very severe contusion injuries to the complete transection, the moderate contusion injury to the double hemi-transection, and the mild contusion injury to the T10 hemi-transection injury. CONCLUSION: Although contusion and transection spinal cord injuries have two completely different pathophysiologies, their injury progress during acute phase follow a similar trend.

Effect of thoracic spinal cord injury on forelimb somatosensory evoked potential.

In this paper, we investigate the forelimbs somatosensory evoked potential (SSEP) signals, which are representative of the integrity of ascending sensory pathways and their stability as well as function, recorded from corresponding cortices, post thoracic spinal cord injury (SCI). We designed a series of distinctive transection SCI to investigate whether forelimbs SSEPs change after right T10 hemi-transection, T8 and T10 double hemi-transection and T8 complete transection in rat model of SCI. We used electrical stimuli to stimulate median nerves and recorded SSEPs from left and right somatosensory areas of both cortices. We monitored pre-injury baseline and verified changes in forelimbs SSEP signals on Days 4, 7, 14, and 21 post-injury. We previously characterized hindlimb SSEP changes for the abovementioned transection injuries. The focus of this article is to investigate the quality and quantity of changes that may occur in the forelimb somatosensory pathways post-thoracic transection SCI. It is important to test the stability of forelimb SSEPs following thoracic SCI because of their potential utility as a proxy baseline for the traumatic SCIs in clinical cases wherein there is no opportunity to gather baseline of the lower extremities. We observed that the forelimb SSEP amplitudes increased following thoracic SCI but gradually returned to the baseline. Despite changes found in the raw signals, statistical analysis found forelimb SSEP signals become stable relatively soon. In summary, though there are changes in value (with p > 0.05), they are not statistically significant. Therefore, the null hypothesis that the mean of the forelimb SSEP signals are the same across multiple days after injury onset cannot be rejected during the acute phase.

Upconversion Nanoparticle-Mediated Optogenetics.

Upconversion nanoparticle-mediated optogenetics enables remote delivery of upconverted visible light from a near-infrared light source to targeted neurons or areas, with the precision of a pulse of laser light in vivo for effective deep-tissue neuromodulation. Compared to conventional optogenetic tools, upconversion nanoparticle-based optogenetic techniques are less invasive and cause reduced inflammation with minimal levels of tissue damage. In addition to the optical stimulation, this design offers simultaneously temperature recording in proximity to the stimulated area. This chapter strives to provide life science researchers with an introduction to upconversion optogenetics, starting from the fundamental concept of photon upconversion and nanoparticle fabrication to the current state-of-the-art of surface engineering and device integration for minimally invasive neuromodulation.

Recent Developments in Prosthesis Sensors, Texture Recognition, and Sensory Stimulation for Upper Limb Prostheses.

Current developments being made in upper limb prostheses are focused on replacing lost sensory information to the amputees. Providing sensory stimulation from the prosthesis can directly improve control over the prosthetic and provide a sense of body ownership. The focus of this review article is on recent developments while including foundational knowledge for some of the critical concepts in neural prostheses. Reported concepts follow the flow of information from sensors to signal processing, with emphasis on texture recognition, and then to sensory stimulation strategies that reestablish the lost sensory feedback loop. Prosthetic sensors are used to detect the physical environment, converting pressure, force, and position into electrical signals. The electrical signals can then be processed in an effort to identify the surrounding environment using distinctive characteristics such as stiffness and texture. In order for the amputee to use this information in a natural manner, there must be real-time sensory stimulation, perception, and motor control of the prosthesis. Although truly complete sensory replacement has not yet been realized, some basic percepts can be partially restored, allowing progress towards a more realistic prosthesis with natural sensations.

Trading baseline with forelimbs somatosensory evoked potential for longitudinal analysis in thoracic transection spinal cord injury.

Patients who suffered from spinal cord injury (SCI) that come to healthcare professionals for diagnosis and treatment do not have electrophysiology baseline of somatosensory evoked potential (SSEP). The SSEP has always been used in research for data comparison to detect onset and severity of the SCI as well as for assessing its progress, endogenous and therapeutic recovery. This unmet need has motivated us to develop a new tool to substitute the baseline data with forelimb SSEP data of the same day. In this study, we report the development and investigation of three distinctive thoracic transections (right T10 hemi-transection (Rxl), left T8 and right T10 double hemi-transection (Dxl) and T8 complete transection (Cxl)) spinal cord injuries in an adult rat model. We used our well-established monitoring methods to obtain SSEP baselines as well as post-injury signals from days 4, 7, 14 and 21. We observed that spectral coherences obtained from non-injured spinal cord pathways are always above 0.8. The spectral coherence is dimensionless measure with values between 0 and 1 and measures the correlation between two time signals in the frequency domain. Analysis of variance (ANOVA) results also showed that there is a significant difference between the spectral coherence componanet means before and after injury with reaching p = 0.05 for Rxl, p = 0.02 for DxI, and p = 0.00 for CxI. Our signal processing enables us to replicate comparable detection of the natural history of injuries longitudinally without the implication of baseline SSEP signals, highlighting the potential of this analysis method for clinical studies.

A Review of Functional Electrical Stimulation Treatment in Spinal Cord Injury.

Functional electrical stimulation (FES) has been widely adopted to elicit muscle contraction in rehabilitation training after spinal cord injury (SCI). Conventional FES modalities include stimulations coupled with rowing, cycling, assisted walking and other derivatives. In this review, we studied thirteen clinical reports from the past 5 years and evaluated the effects of various FES aided rehabilitation plans on the functional recovery after SCI, highlighting upper and lower extremity strength, cardiopulmonary function, and balder control. We further explored potential mechanisms of FES using the Hebbian theory and lumbar locomotor central pattern generators. Overall, FES can be used to improve respiration, circulation, hand strength, mobility, and metabolism after SCI.

Characterization of transection spinal cord injuries by monitoring somatosensory evoked potentials and motor behavior.

Standardization of spinal cord injury (SCI) models is crucial for reproducible injury in research settings and their objective assessments. Basso, Beattie and Bresnahan (BBB) scoring, the traditional behavioral evaluation method, is subjective and susceptible to human error. On the other hand, neuro-electrophysiological monitoring, such as somatosensory evoked potential (SSEP), is an objective assessment method that can be performed continuously for longitudinal studies. We implemented both SSEP and BBB assessments on transection SCI model. Five experimental groups are designed as follows: left hemi-transection at T8, right hemi-transection at T10, double hemi-transection at left T8 and right T10, complete transection at T8 and control group which receives only laminectomy with intact dura and no injury on spinal cord parenchyma. On days 4, 7, 14 and 21 post-injury, first BBB scores in awake and then SSEP signals in anesthetized rats were obtained. Our results show SSEP signals and BBB scores are both closely associated with transection model and injury progression. However, the two assessment modalities demonstrate different sensitivity in measuring injury progression when it comes to late-stage double hemi-transection, complete transection and hemi-transection injury. Furthermore, SSEP amplitudes are found to be distinct in different injury groups and the progress of their attenuation is increasingly rapid with more severe transection injuries. It is evident from our findings that SSEP and BBB methods provide distinctive and valuable information and could be complementary of each other. We propose incorporating both SSEP monitoring and conventional BBB scoring in SCI research to more effectively standardize injury progression.

Visualization of Intra-neuronal Motor Protein Transport through Upconversion Microscopy.

Cargo transport along axons, a physiological process mediated by motor proteins, is essential for neuronal function and survival. A current limitation in the study of axonal transport is the lack of a robust imaging technique with a high spatiotemporal resolution to visualize and quantify the movement of motor proteins in real-time and in different depth planes. Herein, we present a dynamic imaging technique that fully exploits the characteristics of upconversion nanoparticles. This technique can be used as a microscopic probe for the quantitative in situ tracking of retrograde transport neurons with single-particle resolution in multilayered cultures. This study may provide a powerful tool to reveal dynamic neuronal activity and intra-axonal transport function as well as any associated neurodegenerative diseases resulting from mutation or impairment in the axonal transport machinery.

Upconversion amplification through dielectric superlensing modulation.

Achieving efficient photon upconversion under low irradiance is not only a fundamental challenge but also central to numerous advanced applications spanning from photovoltaics to biophotonics. However, to date, almost all approaches for upconversion luminescence intensification require stringent controls over numerous factors such as composition and size of nanophosphors. Here, we report the utilization of dielectric microbeads to significantly enhance the photon upconversion processes in lanthanide-doped nanocrystals. By modulating the wavefront of both excitation and emission fields through dielectric superlensing effects, luminescence amplification up to 5 orders of magnitude can be achieved. This design delineates a general strategy to converge a low-power incident light beam into a photonic hotspot of high field intensity, while simultaneously enabling collimation of highly divergent emission for far-field accumulation. The dielectric superlensing-mediated strategy may provide a major step forward in facilitating photon upconversion processes toward practical applications in the fields of photobiology, energy conversion, and optogenetics.

All-inorganic perovskite nanocrystal scintillators.

The rising demand for radiation detection materials in many applications has led to extensive research on scintillators1-3. The ability of a scintillator to absorb high-energy (kiloelectronvolt-scale) X-ray photons and convert the absorbed energy into low-energy visible photons is critical for applications in radiation exposure monitoring, security inspection, X-ray astronomy and medical radiography4,5. However, conventional scintillators are generally synthesized by crystallization at a high temperature and their radioluminescence is difficult to tune across the visible spectrum. Here we describe experimental investigations of a series of all-inorganic perovskite nanocrystals comprising caesium and lead atoms and their response to X-ray irradiation. These nanocrystal scintillators exhibit strong X-ray absorption and intense radioluminescence at visible wavelengths. Unlike bulk inorganic scintillators, these perovskite nanomaterials are solution-processable at a relatively low temperature and can generate X-ray-induced emissions that are easily tunable across the visible spectrum by tailoring the anionic component of colloidal precursors during their synthesis. These features allow the fabrication of flexible and highly sensitive X-ray detectors with a detection limit of 13 nanograys per second, which is about 400 times lower than typical medical imaging doses. We show that these colour-tunable perovskite nanocrystal scintillators can provide a convenient visualization tool for X-ray radiography, as the associated image can be directly recorded by standard digital cameras. We also demonstrate their direct integration with commercial flat-panel imagers and their utility in examining electronic circuit boards under low-dose X-ray illumination.

Near-infrared deep brain stimulation via upconversion nanoparticle-mediated optogenetics.

Optogenetics has revolutionized the experimental interrogation of neural circuits and holds promise for the treatment of neurological disorders. It is limited, however, because visible light cannot penetrate deep inside brain tissue. Upconversion nanoparticles (UCNPs) absorb tissue-penetrating near-infrared (NIR) light and emit wavelength-specific visible light. Here, we demonstrate that molecularly tailored UCNPs can serve as optogenetic actuators of transcranial NIR light to stimulate deep brain neurons. Transcranial NIR UCNP-mediated optogenetics evoked dopamine release from genetically tagged neurons in the ventral tegmental area, induced brain oscillations through activation of inhibitory neurons in the medial septum, silenced seizure by inhibition of hippocampal excitatory cells, and triggered memory recall. UCNP technology will enable less-invasive optical neuronal activity manipulation with the potential for remote therapy.

Binary temporal upconversion codes of Mn2+-activated nanoparticles for multilevel anti-counterfeiting.

Optical characteristics of luminescent materials, such as emission profile and lifetime, play an important role in their applications in optical data storage, document security, diagnostics, and therapeutics. Lanthanide-doped upconversion nanoparticles are particularly suitable for such applications due to their inherent optical properties, including large anti-Stokes shift, distinguishable spectroscopic fingerprint, and long luminescence lifetime. However, conventional upconversion nanoparticles have a limited capacity for information storage or complexity to prevent counterfeiting. Here, we demonstrate that integration of long-lived Mn2+ upconversion emission and relatively short-lived lanthanide upconversion emission in a particulate platform allows the generation of binary temporal codes for efficient data encoding. Precise control of the particle's structure allows the excitation feasible both under 980 and 808 nm irradiation. We find that the as-prepared Mn2+-doped nanoparticles are especially useful for multilevel anti-counterfeiting with high-throughput rate of authentication and without the need for complex time-gated decoding instrumentation.Luminescent materials that are capable of binary temporal coding are desirable for multilevel anti-counterfeiting. Here, the authors engineer nanoparticles that produce binary color codes on different timescales by combining the long-lived luminescence of Mn2+ with the relatively short-lived emission of lanthanides.

Transcriptome Analysis Reveals Neuroprotective aspects of Human Reactive Astrocytes induced by Interleukin 1ß.

Reactive astrogliosis is a critical process in neuropathological conditions and neurotrauma. Although it has been suggested that it confers neuroprotective effects, the exact genomic mechanism has not been explored. The prevailing dogma of the role of astrogliosis in inhibition of axonal regeneration has been challenged by recent findings in rodent model's spinal cord injury, demonstrating its neuroprotection and axonal regeneration properties. We examined whether their neuroprotective and axonal regeneration potentials can be identify in human spinal cord reactive astrocytes in vitro. Here, reactive astrogliosis was induced with IL1ß. Within 24 hours of IL1ß induction, astrocytes acquired reactive characteristics. Transcriptome analysis of over 40000 transcripts of genes and analysis with PFSnet subnetwork revealed upregulation of chemokines and axonal permissive factors including FGF2, BDNF, and NGF. In addition, most genes regulating axonal inhibitory molecules, including ROBO1 and ROBO2 were downregulated. There was no increase in the gene expression of "Chondroitin Sulfate Proteoglycans" (CSPGs') clusters. This suggests that reactive astrocytes may not be the main CSPG contributory factor in glial scar. PFSnet analysis also indicated an upregulation of "Axonal Guidance Signaling" pathway. Our result suggests that human spinal cord reactive astrocytes is potentially neuroprotective at an early onset of reactive astrogliosis.

Static Magnetic Field Stimulation Enhances Oligodendrocyte Differentiation and Secretion of Neurotrophic Factors.

The cellular-level effects of low/high frequency oscillating magnetic field on excitable cells such as neurons are well established. In contrast, the effects of a homogeneous, static magnetic field (SMF) on Central Nervous System (CNS) glial cells are less investigated. Here, we have developed an in vitro SMF stimulation set-up to investigate the genomic effects of SMF exposure on oligodendrocyte differentiation and neurotrophic factors secretion. Human oligodendrocytes precursor cells (OPCs) were stimulated with moderate intensity SMF (0.3 T) for a period of two weeks (two hours/day). The differential gene expression of cell activity marker (c-fos), early OPC (Olig1, Olig2. Sox10), and mature oligodendrocyte markers (CNP, MBP) were quantified. The enhanced myelination capacity of the SMF stimulated oligodendrocytes was validated in a dorsal root ganglion microfluidics chamber platform. Additionally, the effects of SMF on the gene expression and secretion of neurotrophic factors- BDNF and NT3 was quantified. We also report that SMF stimulation increases the intracellular calcium influx in OPCs as well as the gene expression of L-type channel subunits-CaV1.2 and CaV1.3. Our findings emphasize the ability of glial cells such as OPCs to positively respond to moderate intensity SMF stimulation by exhibiting enhanced differentiation, functionality as well as neurotrophic factor release.

Subcellular electrical stimulation of neurons enhances the myelination of axons by oligodendrocytes.

Myelin formation has been identified as a modulator of neural plasticity. New tools are required to investigate the mechanisms by which environmental inputs and neural activity regulate myelination patterns. In this study, we demonstrate a microfluidic compartmentalized culture system with integrated electrical stimulation capabilities that can induce neural activity by whole cell and focal stimulation. A set of electric field simulations was performed to confirm spatial restriction of the electrical input in the compartmentalized culture system. We further demonstrate that electrode localization is a key consideration for generating uniform the stimulation of neuron and oligodendrocytes within the compartments. Using three configurations of the electrodes we tested the effects of subcellular activation of neural activity on distal axon myelination with oligodendrocytes. We further investigated if oligodendrocytes have to be exposed to the electrical field to induce axon myelination. An isolated stimulation of cell bodies and proximal axons had the same effect as an isolated stimulation of distal axons co-cultured with oligodendrocytes, and the two modes had a non-different result than whole cell stimulation. Our platform enabled the demonstration that electrical stimulation enhances oligodendrocyte maturation and myelin formation independent of the input localization and oligodendrocyte exposure to the electrical field.

Direct Conversion Through Trans-Differentiation: Efficacy and Safety.

Direct conversion through transdifferentiation is a promising cell reprogramming approach that induces a cell lineage conversion among adult cells without passing through an intermediate pluripotent phase. However, there is a need to critically evaluate the efficacy and safety of direct conversion to establish its feasibility as a clinically viable cell reprogramming technique. This review article aims to delineate some critical constraints of direct conversion as a cellular reprogramming approach. We report the most important challenges of lineage reprogramming through direct conversion and divide them into two major sections. The first section explores the obstacles that limit the efficiency of the direct conversion process. In this study, we discuss challenges such as lack of understanding of molecular mechanism and transcriptional control of direct conversion, low proliferative capacity of converted cells, and senescence and apoptosis as critical barriers of direct conversion. The second section focuses on addressing concerns of safety of directly converted cells. We describe issues of transgene load and epigenetic memory retention along with the constraints of currently available validation tools to characterize reprogrammed cells. Each issue mentioned above is evaluated in view of their origin, implications, progress made toward their resolution and scope for development of new strategies to address the constraints of the present technique.